Incorporation of view sharing and KWIC filtering into GRASP-Pro improves spatial resolution of single-shot, multi-TI, late gadolinium enhancement MRI.

While single-shot late gadolinium enhancement (LGE) is useful for imaging patients with arrhythmia and/or dyspnea, it produces low spatial resolution. One approach to improve spatial resolution is to accelerate data acquisition using compressed sensing (CS). Our previous work described a single-shot, multi-inversion time (TI) LGE pulse sequence using radial k-space sampling and CS, but over-regularization resulted in significant image blurring that muted the benefits of data acceleration. The purpose of the present study was to improve the spatial resolution of the single-shot, multi-TI LGE pulse sequence by incorporating view sharing (VS) and k-space weighted contrast (KWIC) filtering into a GRASP-Pro reconstruction. In 24 patients (mean age = 61 ± 16 years; 9/15 females/males), we compared the performance of our improved multi-TI LGE and standard multi-TI LGE, where clinical standard LGE was used as a reference. Two clinical raters independently graded multi-TI images and clinical LGE images visually on a five-point Likert scale (1, nondiagnostic; 3, clinically acceptable; 5, best) for three categories: the conspicuity of myocardium or scar, artifact, and noise. The summed visual score (SVS) was defined as the sum of the three scores. Myocardial scar volume was quantified using the full-width at half-maximum method. The SVS was not significantly different between clinical breath-holding LGE (median 13.5, IQR 1.3) and multi-TI LGE (median 12.5, IQR 1.6) (P = 0.068). The myocardial scar volumes measured from clinical standard LGE and multi-TI LGE were strongly correlated (coefficient of determination, R2 = 0.99) and in good agreement (mean difference = 0.11%, lower limit of the agreement = -2.13%, upper limit of the agreement = 2.34%). The inter-rater agreement in myocardial scar volume quantification was strong (intraclass correlation coefficient = 0.79). The incorporation of VS and KWIC into GRASP-Pro improved spatial resolution. Our improved 25-fold accelerated, single-shot LGE sequence produces clinically acceptable image quality, multi-TI reconstruction, and accurate myocardial scar volume quantification.

A theoretical framework for retrospective T2∗ correction to the arterial input function in quantitative myocardial perfusion MRI.

PURPOSE: To develop and evaluate a flexible, Bloch-equation based framework for retrospective T2∗ correction to the arterial input function (AIF) obtained with quantitative cardiac perfusion pulse sequences. METHODS: Our framework initially calculates the gadolinium concentration [Gd] based on T1 measurements alone. Next, T2∗ is estimated from this initial calculation of [Gd] while assuming fast water exchange and using the literature native T2 and static magnetic field variation (ΔB0 ) values. Finally, the [Gd] is recalculated after performing T2∗ correction to the Bloch equation signal model. Using this approach, we performed T2∗ correction to historical phantom and in vivo, dual-imaging perfusion data sets from 3 different patient groups obtained using different pulse sequences and imaging parameters. Images were processed to quantify both the AIF and resting myocardial blood flow (MBF). We also performed a sensitivity analysis of our T2∗ correction to ±20% variations in native T2 and ΔB0 . RESULTS: Compared with the ground truth [Gd] of phantom, the normalized root-means-square-error (NRMSE) in measured [Gd] was 5.1%, 1.3%, and 0.6% for uncorrected, our corrected, and Kellman's corrected, respectively. For in vivo data, both the peak AIF (7.0 ± 3.0 mM vs. 8.6 ± 7.1 mM, 7.2 ± 0.9 mM vs. 8.6 ± 1.7 mM, 7.7 ± 1.8 mM vs. 10.3 ± 5.1 mM, P < .001) and resting MBF (1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.2 ± 0.1 mL/g/min vs. 0.9 ± 0.1 mL/g/min, P < .001) values were significantly different between uncorrected and corrected for all 3 patient groups. Both the peak AIF and resting MBF values varied by <5% over the said variations in native T2 and ΔB0 . CONCLUSION: Our theoretical framework enables retrospective T2∗ correction to the AIF obtained with dual-imaging, cardiac perfusion pulse sequences.

An empirical method for reducing variability and complexity of myocardial perfusion quantification by dual bolus cardiac MRI.

PURPOSE: Myocardial perfusion can be quantified using the "dual bolus" technique, which uses two separate contrast boluses to avoid signal nonlinearity in the blood pool. This technique relies on knowing the precise ratio of contrast concentrations between the two boluses. In this study, we investigated the variability found in these ratios, as well as the error it introduces, and developed a method for correction. METHODS: Five dogs received dual bolus myocardial perfusion MRI scans. Perfusion was calculated separately using assumed contrast dilution ratios and empirically determined contrast ratios. Perfusion was compared with reference standard fluorescent microspheres. The same technique was then applied to a cohort of six patients with no significant coronary artery stenosis by cardiac catheterization. RESULTS: Assumed contrast dilution ratios were 10:1 for all animal and patient scans. Empirically derived contrast ratios were significantly different for animal (8.51:1 ± 1.53:1, P < 0.001) and patient scans (7.32:1 ± 2.27:1, P < 0.01). Incorporating empirically derived ratios for animal scans improved correlation with microspheres from 0.84 to 0.90 (P < 0.05). CONCLUSION: Variability in dual bolus contrast concentration ratios is an important source of experimental error, especially outside of a carefully controlled laboratory setting. Empirically deriving the correct ratio is feasible and improves the accuracy of quantitative perfusion measurements. Magn Reson Med 77:2347-2355, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.

IMPORTANCE: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. OBJECTIVE: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. INTERVENTIONS: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. MAIN OUTCOMES AND MEASURES: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. RESULTS: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

Absolute quantification of myocardial blood flow with constrained estimation of the arterial input function.

PURPOSE: To evaluate the performance of the constrained alternating minimization with model (CAMM) method for estimating the input function from the myocardial tissue curves. MATERIALS AND METHODS: Myocardial perfusion imaging was performed on seven canine models of coronary artery disease in 15 imaging sessions. In each session, stress was induced with intravenous infusion of adenosine and a variable occluder created coronary artery stenosis. A dual bolus protocol was used for each acquisition, and input functions were then estimated using the CAMM method with data acquired from the high dose scan following each imaging session. For each acquisition, myocardial blood flow was measured by injected microspheres. RESULTS: The dual bolus and CAMM-derived flows were not significantly different (P = 0.18), and the correlation between the two methods was high (r = 0.97). The correlation between the dual bolus and CAMM methods and microsphere measurements was lower than that for the two MR methods (r = 0.53; r = 0.43, respectively). CONCLUSION: The CAMM method presented here shows promise in estimating myocardial blood flow in patients with coronary artery disease at stress with a single injection and without any specialized acquisitions. Further work is needed to validate the approach in a clinical setting.

Identification of Cardiac Fibrosis in Young Adults With a Homozygous Frameshift Variant in SERPINE1.

Importance: Cardiac fibrosis is exceedingly rare in young adults. Identification of genetic variants that cause early-onset cardiomyopathy may inform novel biological pathways. Experimental models and a single case report have linked genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), a downstream target of cardiac transforming growth factor ß, with cardiac fibrosis. Objective: To perform detailed cardiovascular phenotyping and genotyping in young adults from an Amish family with a frameshift variant (c.699_700dupTA) in SERPINE1, the gene that codes for PAI-1. Design, Setting, and Participants: This observational study included participants from 3 related nuclear families from an Amish community in the primary analysis and participants from the extended family in the secondary analysis. Participants were recruited from May 2015 to December 2016, and analysis took place from June 2015 to June 2020. Main Outcomes and Measures: (1) Multimodality cardiovascular imaging (transthoracic echocardiography and cardiac magnetic resonance imaging), (2) whole-exome sequencing, and (3) induced pluripotent stem cell-derived cardiomyocytes. Results: Among 17 participants included in the primary analysis, the mean (interquartile range) age was 23.7 (20.9-29.9) years and 9 individuals (52.9%) were confirmed to be homozygous for the SERPINE1 c.699_700dupTA variant. Late gadolinium enhancement was present in 6 of 9 homozygous participants (67%) with absolute PAI-1 deficiency vs 0 of 8 in the control group (P = .001). Late gadolinium enhancement patterns tended to be dense and linear, usually subepicardial but also midmyocardial and transmural with noncoronary distributions. Targeted whole-exome sequencing analysis identified that homozygosity for c.699_700dupTA SERPINE1 was the only shared pathogenic variant or variant of uncertain significance after examination of cardiomyopathy genes among those with late gadolinium enhancement. Induced pluripotent stem cell-derived cardiomyocytes from participants homozygous for the SERPINE1 c.699_700dupTA variant exhibited susceptibility to cardiomyocyte injury in response to angiotensin II (increased transforming growth factor ß1 secretion and release of lactate dehydrogenase) compared with control induced pluripotent stem cell-derived cardiomyocytes. In a secondary analysis based on echocardiography in 155 individuals across 3 generations in the extended family, no difference in global longitudinal strain was observed in carriers for the SERPINE1 c.699_700dupTA variant compared with wild-type participants, supporting an autosomal recessive inheritance pattern. Conclusions and Relevance: In this study, a highly penetrant, autosomal recessive, cardiac fibrosis phenotype among young adults with homozygous frameshift variant for SERPINE1 was identified, suggesting an optimal range of PAI-1 levels are needed for cardiac homeostasis.

Diffuse right ventricular fibrosis in heart failure with preserved ejection fraction and pulmonary hypertension.

AIMS: While right ventricular (RV) dysfunction is associated with worse prognosis in co-morbid pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF), the mechanisms driving RV dysfunction are unclear. We evaluated the extent and clinical correlates of diffuse RV myocardial fibrosis in PH-HFpEF, as measured by cardiovascular magnetic resonance-derived extracellular volume (ECV). METHODS AND RESULTS: We prospectively enrolled participants with PH-HFpEF (n = 14), pulmonary arterial hypertension (PAH; n = 13), and controls (n = 8). All participants underwent high-resolution cardiovascular magnetic resonance, and case subjects (PH-HFpEF and PAH) additionally underwent right heart catheterization. T1 mapping was performed using high-resolution modified look-locker inversion recovery with a 1 × 1 mm2 in-plane resolution. RV free wall T1 values were quantified, and ECV was calculated. Participants with PH-HFpEF were older and carried higher rates of hypertension and obstructive sleep apnoea than those with PAH. While RV ECV was similar between PH-HFpEF and PAH (33.1 ± 8.0 vs. 34.0 ± 4.5%; P = 0.57), total pulmonary resistance was lower in PH-HFpEF compared with PAH [PH-HFpEF: 5.68 WU (4.70, 7.66 WU) vs. PAH: 8.59 WU (8.14, 12.57 WU); P = 0.01]. RV ECV in PH-HFpEF was associated with worse indices of RV structure (RV end-diastolic volume: r = 0.67, P = 0.01) and RV function (RV free wall strain: r = 0.59, P = 0.03) but was not associated with RV afterload (total pulmonary resistance: r = 0.08, P = 0.79). Conversely, there was a strong correlation between RV ECV and RV afterload in PAH (r = 0.57, P = 0.04). CONCLUSIONS: Diffuse RV fibrosis, as measured by ECV, is present in PH-HFpEF and is associated with adverse RV structural and functional remodelling but not degree of pulmonary vasculopathy. In PH-HFpEF, diffuse RV fibrosis may occur out of proportion to the degree of RV afterload.

Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis.

PURPOSE: To evaluate the utility of cardiac magnetic resonance (CMR) T1 mapping in early systemic sclerosis (SSc) and its association with skin score. METHODS: Twenty-four consecutive patients with early SSc referred for cardiovascular evaluation and 12 controls without SSc were evaluated. All patients underwent cine, T1 mapping, and late gadolinium enhanced (LGE) CMR imaging. T1 mapping indices were compared between SSc patients and controls (extracellular volume fraction [ECV], gadolinium partition coefficient [λ], pre-contrast T1, and post-contrast T1). The association between T1 mapping parameters and the modified Rodnan skin score (mRSS) was determined. RESULTS: There were no significant differences in cardiac structure/function between SSc patients and controls on cine imaging, and 8/24 (33%) SSc patients had evidence of LGE (i.e., focal myocardial fibrosis). Of the T1 mapping parameters (indices indicative of diffuse myocardial fibrosis), ECV differentiated SSc patients from controls the best, followed by λ, even when the eight SSc patients with LGE were excluded. ECV had a sensitivity and specificity of 75% and 75% for diffuse myocardial fibrosis (optimal abnormal cut-off value of >27% [area under ROC curve=0.85]). In the 16 patients without evidence of LGE, each of the 4 CMR T1 mapping parameters (ECV, λ, Pre-T1 and Post-T1) correlated with mRSS (R=0.51-0.65, P=0.007-0.043), indicating a correlation between SSc cardiac and skin fibrosis. CONCLUSIONS: The four T1 mapping indices are significantly correlated with mRSS in patients with early SSc. Quantification of diffuse myocardial fibrosis using ECV should be considered as a marker for cardiac involvement in SSc clinical studies.

The Kinetics of Circulating Monocyte Subsets and Monocyte-Platelet Aggregates in the Acute Phase of ST-Elevation Myocardial Infarction: Associations with 2-Year Cardiovascular Events.

In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering ST-elevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up.Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14++CD16+ monocytes and CD14++CD16+ MPA were observed, with peak levels on day 2. During a median follow-up of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14++CD16+ monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; P = 0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; P = 0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; P = 0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; P = 0.02]), as well as increased levels of CD14++CD16+ MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events.In conclusion, our data show the expansion of the CD14++CD16+ monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies after STEMI.

A Comparison of Theory-Based and Experimentally Determined Myocardial Signal Intensity Correction Methods in First-Pass Perfusion Magnetic Resonance Imaging.

OBJECTIVES: To evaluate the impact of correcting myocardial signal saturation on the accuracy of absolute myocardial blood flow (MBF) measurements. MATERIALS AND METHODS: We performed 15 dual bolus first-pass perfusion studies in 7 dogs during global coronary vasodilation and variable degrees of coronary artery stenosis. We compared microsphere MBF to MBF calculated from uncorrected and corrected MRI signal. Four correction methods were tested, two theoretical methods (Th1 and Th2) and two empirical methods (Em1 and Em2). RESULTS: The correlations with microsphere MBF (n = 90 segments) were: uncorrected (y = 0.47x + 1.1, r = 0.70), Th1 (y = 0.53x + 1.0, r = 0.71), Th2 (y = 0.62x + 0.86, r = 0.73), Em1 (y = 0.82x + 0.86, r = 0.77), and Em2 (y = 0.72x + 0.84, r = 0.75). All corrected methods were not significantly different from microspheres, while uncorrected MBF values were significantly lower. For the top 50% of microsphere MBF values, flows were significantly underestimated by uncorrected SI (31%), Th1 (25%), and Th2 (19%), while Em1 (1%), and Em2 (9%) were similar to microsphere MBF. CONCLUSIONS: Myocardial signal saturation should be corrected prior to flow modeling to avoid underestimation of MBF by MR perfusion imaging.

Leakage and water exchange characterization of gadofosveset in the myocardium.

PURPOSE: To determine the compartmentalization of the blood pool agent gadofosveset and the effect of its transient binding to albumin on the quantification of steady-state fractional myocardial blood volume (fMBV). METHODS: Myocardial vascular fraction measurements were simulated assuming the limiting cases (slow or fast) of two-compartment water exchange for different contrast agent injection concentrations, binding fractions, bound and free relaxivities, and true cardiac vascular fractions. fMBV was measured in five healthy volunteers (4 males, 1 female, average age 33) at 1.5T after administration of five injections of gadofosveset. The measurements in the volunteers were retrospectively compared to measurements of fMBV after three serial injections of the ultra-small, paramagnetic iron oxide (USPIO) blood pool agent ferumoxytol in an experimental animal. The true fMBV and exchange rate of water protons in both human and animal data sets was determined by chi square minimization. RESULTS: Simulations showed an error in the measurement of fMBV due to partial binding of gadofosveset of less than 30%. Measured fMBV values over-estimate simulation predictions, and approach cardiac extracellular volume (22%), which suggests that the intravascular assumption may not be appropriate for the myocardium, although it may apply to more distal perfusion beds. In comparison, fMBV measured with ferumoxytol (5%, with slow water proton exchange across vascular wall) agree with published values of myocardial vascular fraction. Further comparison between myocardium relaxation rates induced by gadofosveset and by other extracellular and intravascular contrast agents showed that gadofosveset behaves like an extracellular contrast agent. CONCLUSIONS: The distribution of the volunteer data indicates that a three-compartment model, with slow water exchange of gadofosveset and water protons between the vascular and interstitial compartments, and fast water exchange between the interstitium and the myocytes, is appropriate. The ferumoxytol measurements indicate that this USPIO is an intravascular contrast agent that can be used to quantify myocardial blood volume, with the appropriate correction for water exchange using a two-compartment water exchange model.